Clinical Characteristics of a Case Series of Ocular Syphilis With 3 Cases Requiring Multiple Vitrectomies After Late Diagnosis

Abstract

Purpose:

This work describes the characteristics and unique features of ocular syphilis.

Methods:

Ten serologically proven cases of ocular syphilis were retrospectively analyzed.

Results:

Eighteen eyes of 10 patients were affected. Nine of 10 patients were male and the mean age was 58 years (range, 36-81 years). HIV antibody testing was positive in 3 patients (30%). Five cases were first diagnosed by an ophthalmologist. One patient presented with a syphilitic rash. The most common ocular findings were panuveitis (n = 6) and cystoid macular edema (n = 4). Ocular involvement was unilateral in 2 cases and bilateral in 8. Best-corrected visual acuity improved in 13 of 18 eyes (72%) after treatment. Three cases developed recurrent retinal detachments that required repair with silicone oil.

Conclusions:

Most cases were HIV negative. Syphilitic uveitis can be the initial presentation of syphilis without classic systemic manifestation. Ophthalmologists play an important role in the diagnosis and treatment of syphilis.

Introduction

Syphilis, caused by Treponema pallidum, is a 3-stage infection with variable presentations known for challenges in diagnosis. Ocular involvement is uncommon, presenting in 0.6% of US syphilis cases, but can result in vision loss and even blindness if untreated. ¹ The prevalence of syphilis in the United States has increased dramatically from 2.1 to 9.5 cases per 100 000 population from 2001 to 2017, reaching the highest rates in more than 20 years. ² This resurgence in syphilis cases in the United States corresponds with recent reports of ocular syphilis in nearly all regions of the globe, including the United Kingdom, Australia, South Africa, France, and China. ^{1,3 -8}

Ocular syphilis classically presents as uveitis in secondary or tertiary syphilis and has been shown to affect all structures of the eye. ⁹ Although the timing of syphilis progression varies, a recent study has recorded a median time to ocular symptom development of 11 months following infection. ¹⁰ Ocular syphilis cases have presented with nonspecific initial symptoms such as tongue chancre, painless vision loss, jaundice, and ocular involvement as varied as anterior uveitis to acute retinal necrosis. ^{11 -14} Ocular syphilis is highly associated with neurosyphilis and HIV-positive status, although it can occur with isolated syphilis infection as well. ^15,16

A presumptive diagnosis is often achieved with nontreponemal tests such as the Venereal Disease Research Laboratory test (VDRL) or rapid plasma reagin (RPR) or treponemal tests such as the Fluorescent Treponemal Antibody Absorption or T pallidum immunoglobulin G. ¹⁷ Confirmation of ocular syphilis can be achieved with aqueous fluid polymerase chain reaction testing for T pallidum DNA or dark-field microscopic visualization of the spirochetes.

According to current US Centers for Disease Control and Prevention treatment guidelines, ocular syphilis should be treated as neurosyphilis with 10 to 14 days of intravenous (IV) penicillin G, with follow-up testing at 6 and 12 months. ¹⁷ Better visual outcomes following treatment are associated with a greater visual acuity (VA) at diagnosis, and poorer outcomes are associated with a delay in diagnosis and treatment. ^{18 -20} Severe cases with diffuse inflammation may present with rhegmatogenous retinal detachment necessitating a combination of vitrectomy, scleral buckling, and endolaser photocoagulation. ²¹

Here, we present a case series of 10 patients with ocular syphilis, highlighting important clinical characteristics. It is important to include ocular syphilis in the differential for ocular abnormalities, remaining aware of variability in initial presentation and ophthalmologic management of a long and potentially complicated disease course. Although there are several case reports in the literature, this case series demonstrates the breadth of manifestations and outcomes in patients with ocular syphilis.

Methods

Ten patients with ocular syphilis who presented to the University of Minnesota Department of Ophthalmology and Minneapolis Veterans Affairs Hospital between 2015 and 2019 were retrospectively analyzed. All cases had ocular involvement and had serologic positivity for syphilis infection. Demographics, laboratory results, ocular findings, extraocular findings, and treatment course were recorded. The study was approved by the University of Minnesota Institutional Review Board (reference 1612E01721).

Results

Eighteen eyes of 10 patients with ocular syphilis were analyzed (Table 1). Nine patients were male and 1 was female. The mean age was 58 years (range, 36-81 years). HIV antibody testing was positive in 3 patients. Five cases of syphilis were first diagnosed by an ophthalmologist. All patients presented to an ophthalmologist with 1 or more of the following symptoms: eye pain, blurry vision, or redness. The most common presenting symptoms were blurry vision (10/10) and redness (7/10). The most common ocular finding was panuveitis (6/10). Other ocular findings included cystoid macula edema in 4 of 10 cases, posterior synechiae (3/10), anterior uveitis (2/10), scleritis (1/10), episcleritis (1/10), and interstitial keratitis (1/10) (Figure 1). Posterior placoid choroiditis was found in 2 cases (Figures 2- 4). Eight patients had bilateral involvement and 2 had unilateral involvement. One presented with a typical syphilitic maculopapular rash on the trunk, hands, and feet. Best-corrected VA improved in 13 of 18 eyes (72%). Mean best-corrected VA in affected eyes was 1.51 logarithm of the minimum angle of resolution (logMAR) (20/630 Snellen) at presentation and 0.70 logMAR (20/100 Snellen) at most recent evaluation.

Table 1.

Summary of Ocular Syphilis Cases.

Case	Age, y, sex	HIV status	Known syphilis diagnosis at presentation?	CSF VDRL	Presenting symptoms	BCVA at presentation	Ocular findings	PPV performed?	Follow-up, mo	BCVA final follow-up
1	69, M	Negative	Yes	Unknown	Left eye: blurry vision, redness, pain, tearing	OD: 20/30 OS: 5/200	Left eye: anterior uveitis, cystoid macular edema	Yes	5	OD: 20/40 OS: 10/200
2	62, M	Negative	Yes	Positive	Each eye: blurry vision, redness	OD: 4 ft/200 OS: 2 ft/200	Each eye: panuveitis, cystoid macular edema	No	3	OD: 20/300 OS: 3/200
3	49, M	Positive	Yes	Positive	Left eye: pain, redness	OD: 20/20 OS: 20/70	Left eye: episcleritis, interstitial keratitis, posterior placoid maculopathy, panuveitis, retinal vessel leakage	No	28	OD: 20/40 +1 OS: 20/100 –1
4	43, M	Negative	No	Positive	Each eye: pain, blurry vision, swelling, drainage	OD: HM OS: LP	Each eye: posterior synechiae, panuveitis, posterior placoid choroiditis	Yes	21	OD: 6 ft/200E OS: 20/200
5	36, M	Positive	Yes	Positive	Each eye: redness, irritation	OD: 20/80 OS: 20/200	Each eye: posterior synechiae, panuveitis, cystoid macular edema	No	9.5	OD: 20/100 OS: 20/60
6	69, M	Negative	Yes	Positive	Each eye: pain Left eye: blurry vision, black spot, floaters	OD: 20/30 +3 OS: CF at 5 ft	Right eye: cotton-wool spots Left: optic nerve pallor	No	13.5	OD: 20/30 –2 OS: 20/25 +2
7	81, M	Negative	No	Negative	Each eye: redness, irritation Right eye: blurry vision	OD: HM OS: 20/20	Each eye: posterior placoid chorioretinitis Right eye: posterior vitreous detachment, serous detachment with intraretinal hemorrhage	No	25.5	OD: 20/20 –1 OS: 20/20
8	75, F	Negative	No	Negative	Each eye: blurry vision Left eye: redness, pain	OD: 20/150 OS: CF at 1 ft	Each eye: peripheral keratitis Left eye: diffuse scleritis, anterior uveitis, posterior synechiae	No	2.5	OD: 20/80 OS: 3 ft/200
9	50, M	Negative	No	Positive	Each eye: blurry vision	OD: 20/50 OS: 20/500	Each eye: panuveitis, posterior placoid choroiditis, vessel leakage	No	1	OD: 20/20 –2 OS: 20/40 +1
10	47, M	Positive	No	Positive	Each eye: blurry vision	OD: 20/500 OS: HM	Each eye: posterior synechiae, panuveitis, cystoid macular edema	Yes	23	OD: 20/50 –1 OS: 20/80

Abbreviations: BCVA, best-corrected visual acuity; CF, counting fingers; CSF, cerebrospinal fluid; F, female; HM, hand motions; LP, light perception; M, male; OD, right eye; OS, left eye; VDRL, Venereal Disease Research Lab.

Figure 1.

Slit-lamp photographs of the left eye (case 3) demonstrating (left) persistent scleral injection after 2.5% phenylephrine administration and (right) interstitial keratitis with 360° dense anterior midstromal peripheral haze with corneal neovascularization, and near-360° iris posterior synechiae. Photographs were taken 11 days after diagnosis of ocular syphilis.

Figure 2.

Widefield fundus photograph of the right eye demonstrating posterior placoid chorioretinitis, a classic presentation of ocular syphilis, seen in case 4.

Figure 3.

Fundus photograph of the left eye in case 9 on presentation, demonstrating yellow posterior placoid chorioretinal lesion involving the macula and superior to optic nerve head.

Figure 4.

Fundus autofluorescence of the left eye in case 9 demonstrating peripapillary hyperautofluorescence with patchy hyperautofluorescence inferonasally and parafoveally with temporal macula and peripheral retina involvement.

Seven patients received 2 weeks of IV penicillin and had follow-up with the ophthalmology department after discharge. One patient received 2 weeks of IV ceftriaxone after discontinuing penicillin because of thrombocytopenia and followed up with an ophthalmologist. One patient received penicillin treatment 2 years prior at an unknown site and had not been seen for persistent ocular symptoms until presentation. Another patient received penicillin treatment 1 year before the onset of ocular symptoms.

Nine of 10 patients had lumbar puncture. On lumbar puncture, 7 patients had cerebrospinal fluid (CSF) VDRL titers indicating neurosyphilis, and 2 patients had titers negative for neurosyphilis. The lumbar puncture history is unknown for 1 patient. Three patients were diagnosed with retinal detachment, 2 with unilateral detachments, and 1 with a bilateral detachment. All 3 underwent vitrectomy with silicone oil and retinectomy. All 3 patients had recurrent retinal detachments in their affected eyes that required a second surgery (Figures 5 and 6). One patient required lensectomy, anterior segment reconstruction in one eye, and cataract extraction in the other because of known iatrogenic morbidity from the first set of vitrectomies. Notably, 1 patient underwent vitrectomy for severe vitritis suspicious for ocular syphilis prior to diagnosis. In this case, the diagnosis of ocular syphilis was made with broad-species bacterial polymerase chain reaction from vitreous biopsy following the procedure.

Figure 5.

Preoperative ultrasound B-scans of case 4 show (A) right-eye funnel detachment with bridging membranes and (B) left-eye tractional retinal detachment with subretinal exudation and dense vitreous debris. (C and D) Seven-month postoperative scans showing attached retina OD, right eye; OS, left eye.

Figure 6.

Widefield fundus photograph of left eye in case 4 taken 27 days after the second pars plana vitrectomy with retinectomy demonstrating significant scarring with posterior ring fibrosis.

Conclusions

Over the past 2 decades, the United States has seen a resurgence of syphilis infections. ¹ Correspondingly, since 2015 there have been increasing reports of ocular syphilis, which has led to heightened surveillance for the disease. ¹ Our case series included 10 patients with ocular syphilis. Nine of the patients in this study were male, which is consistent with the national predominance of ocular syphilis in men. ² Although new syphilis infections may be more common in men who have sex with men, this series included a heterosexual woman and 2 heterosexual males. Prior studies have reported a high prevalence of ocular syphilis in HIV-infected men. ¹⁶ In this series, however, only 3 patients were positive for HIV. It is important to recognize that, although HIV and syphilis share similar risk factors, providers should still be vigilant in screening for syphilis in patients who have tested negative for HIV. Additionally, if a patient is diagnosed with ocular syphilis, testing for HIV should also be considered.

The mean age of patients in this study was 58 years, which is consistent with other national reports from the United States and the United Kingdom. ^1,3 The greatest rates of primary and secondary syphilis nationally are seen in young adults aged 25 to 29 years, but the reasons for ocular syphilis typically presenting in older age groups are not well understood. ² It is possible that older patients are more susceptible to ocular involvement of syphilis because of decreased immune response, or that an underlying infection may be latent for a longer duration prior to presentation.

Ocular involvement can occur at all stages of syphilis. This can make ocular syphilis particularly challenging to diagnose because patients may present to a primary care provider or emergency department with visual symptoms in the absence of other systemic manifestations of syphilis. In this case series, all 10 patients presented with ocular symptoms that prompted an evaluation for syphilis. Only 1 patient presented with systemic signs, specifically a syphilitic rash involving the palms and soles of the feet, consistent with secondary syphilis. Although this patient also presented with hearing loss, no patients presented with progressive ataxia or syphilitic myelopathy, which are typical for neurosyphilis.

Ocular syphilis can affect all anatomic locations of the eye. In our case series, panuveitis was the most common finding, consistent with other published reports. ⁹ The 2 patients in the series with HIV had bilateral panuveitis, consistent with a previous work suggesting HIV-infected patients with ocular syphilis may have more diffuse ocular inflammation. ¹⁵ Seven of the 10 patients (70%) had bilateral involvement, compared with 56% bilateral involvement in the British Ocular Syphilis Study. ³

Because syphilis is a systemic, multistage disease, it may not always be considered with nonspecific ocular complaints. In this series, 5 cases of syphilis were first diagnosed by an ophthalmologist. Testing for syphilis should be considered in any patient with ocular inflammation. It is also important to keep syphilis in the differential diagnosis of patients who may have had a prior syphilis evaluation with negative results. One patient in this series tested negative for syphilis 1 year prior and presented with episcleritis that was later diagnosed as syphilitic. Two other patients had negative RPR tests within 4 months prior to ocular syphilis diagnosis. These cases highlight the added value of screening for syphilis even with recent negative results. It is important to note that treponemal tests such as Fluorescent Treponemal Antibody Absorption or T pallidum hemagglutination assay are more appropriate for screening because of increased sensitivity, whereas the nontreponemal tests, RPR and VDRL, are more useful for monitoring response to treatment. ¹⁷

Most cases in this series had positive CSF VDRL titers prior to treatment of neurosyphilis. The 2 patients with negative CSF VDRL findings, however, were still treated with the neurosyphilis protocol of 2 weeks of IV penicillin. CSF VDRL findings are not necessary for the diagnosis of ocular syphilis but are recommended by the US Centers for Disease Control and Prevention to gauge response to treatment. ¹⁷ In practice, however, rates of lumbar puncture for CSF VDRL titers have been reported at 45% in immunocompetent patients testing negative for HIV and 66% in patients testing positive for HIV. ¹ Although no specific serological criteria exist for treatment success or failure, a lack of CSF studies may increase risks of disease recurrence. One patient in this series who did not have CSF studies returned to the ophthalmology department with worsening symptoms after suboptimal initial therapy with ceftriaxone and doxycycline, and subsequently underwent 2 additional weeks of IV penicillin. Negative posttreatment CSF VDRL titers should be used to confirm response to therapy, especially if pretreatment CSF VDRL titers were positive. Surveillance of patients after treatment is also essential.

Early treatment of ocular syphilis is important for improvement in vision, because delayed diagnosis and treatment are associated with poorer visual outcomes. ^{18 -20} Most patients in this series had improved VA after treatment. The most severe case, which required multiple vitrectomies and retinectomies, had a delay in diagnosis and treatment of syphilis that ultimately resulted in severe visual impairment.

Syphilitic uveitis can be the initial presentation of syphilis without obvious systemic manifestations. Ophthalmologists play an important role in the diagnosis and treatment of syphilis, and patients with syphilis experiencing ocular symptoms must be treated and examined by an ophthalmologist. Ocular manifestations of syphilis have the potential to be highly debilitating, so it is important to recognize and treat syphilis early to preserve sight whenever possible.